Hypoxia during gestation is a common stress to maternal cardiovascular homeostasis and causes aberrant uterine vascular hemodynamics and an increased risk of preeclampsia and abnormal fetal development. Recent studies in sheep have demonstrated that chronic hypoxia during gestation causes a significant decrease in estrogen receptor 1 (ER1) expression in uterine arteries, and inhibits the steroid hormone-mediated adaptation of myogenic tone in uterine arteries in pregnancy. However, the molecular mechanisms remain poorly understood. Our preliminary studies suggest that chronic hypoxia increases promoter methylation of the ER1 gene in the uterine artery. DNA methylation is a chief mechanism in epigenetic modification of gene expression patterns. Although methylation of the ER1 promoter has been reported to occur as a direct function of physiological regulation in several tissue types and as part of a pathological progression of numerous types of cancerous tissues, little is known about the epigenetic regulation of ER1 gene expression pattern in vascular smooth muscle and its functional consequences. The proposed studies will address these major gaps in our knowledge and test the hypothesis that chronic hypoxia during gestation causes aberrant promoter methylation and ER1 gene repression resulting in heightened myogenic tone of the uterine artery in pregnancy. Three specific aims are proposed to determine whether: 1) long-term high altitude hypoxia during gestation increases the promoter methylation resulting in ER1 gene repression, 2) prolonged hypoxia has direct causal effects on the heightened promoter methylation and ER1 gene repression, and 3) hypoxia- mediated promoter methylation and ER1 gene repression inhibit the steroid hormone-mediated adaptation of pressure-dependent myogenic tone in the uterine arteries in pregnancy. The results will not only significantly advance our knowledge of the molecular mechanisms underlying aberrant uteroplacental circulation and hence improve our understanding of the pregnancy complications associated with hypoxia, but also provide exciting novel insights into the epigenetic mechanisms regulating ER1 gene expression patterns in vascular smooth muscle and hence a comprehensive understanding of the role of ER1 in the estrogen-mediated protective effect of vascular function in general. PUBLIC HEALTH RELEVANCE: Hypoxia during gestation is a common stress to maternal cardiovascular homeostasis and increases the risk of preeclampsia and fetal intrauterine growth restriction. The proposed studies will provide new insights into the molecular mechanisms underlying aberrant uteroplacental circulation caused by hypoxia in pregnancy and suggest new direction in the clinical management of the pregnancy complications associated with hypoxia, thereby reducing perinatal morbidity while improving maternal health and neonatal outcome.